Cholinergic Drugs

Cholinergic Stimulating Agents:

Acetylcholine is the chemical transmitter for nerves of the parasympathetic, somatic, preganglionic sympathetic, and parts of the central nervous system. Acetylcholine is synthesized by the transfer of an acetyl group from acetyl CoA to choline, a normal constituent of the diet.

Acetylcholine is concentrated in large amounts in presynaptic vesicles, which release their contents into the synapse when voltage-gated calcium channels open in response to membrane depolarization.

Upon interaction with the receptor, acetylcholine produces an influx of sodium through a ligand-gated ion channel which sends the impulse.

After acetylcholine interacts with the cholinergic receptor it is very rapidly hydrolyzed by the enzyme acetylcholinesterase. The hydrolysis reaction is the reverse of the synthesis reaction except that choline and acetic acid are products. The choline is retaken up by the nerve ending where it is reused for synthesis of new molecules of acetylcholine.

Acetylcholine acts on two vastly different classes of receptors - nicotinic receptors (with two subtypes, one at the neuromuscular junction of skeletal muscle, the other within ganglia and the CNS), and muscarinic receptors (widely distributed within both peripheral and central nervous systems). Muscarinic receptors originally were distinguished from nicotinic receptors by the selectivity of the agonists muscarine and nicotine respectively. Notice the similarities in structure for all three of these compounds.

Although there appears to be at least two cholinergic receptor sites, they are similar enough to be considered as one. The acetylcholine interacts with the receptor site through ionic attraction of the positive nitrogen, polar attraction of the ester group, and through hydrophobic interactions with the methyl groups. 

Stimulation:

Stimulation of cholinergic nerves is achieved either directly or indirectly. Direct acting agents (agonists) activate the receptor site by mimicking the effects of acetylcholine. Cholinesterase inhibitors act indirectly by preventing the enzyme from hydrolyzing (inactivating) acetylcholine at the receptor site. This inhibition permits the buildup of acetylcholine and results in more intensive and prolonged activation of the receptor site. The effects of cholinergic stimulation include: vasodilation of blood vessels; slower heart rate; constriction of bronchioles and increased secretion of mucus in the respiratory tract; intestinal cramps; secretion of salvia; sweat and tears; and constriction of eye pupils.

Direct Acting Cholinergic Agents - Agonists:

Direct acting cholinergic agents act as agonists and initiate stimulant type responses at the receptor site. Direct stimulation of acetylcholine receptors is achieved by: Arecholine, Pilocarpine, Urecholine(Betanechol), Carbachol, Choline, Metacholine, Mushrooms (Boletus sp., Clitocybe sp. , Inocybe sp.)

Drugs: Urecholine and philocarpine are direct acting drugs. Urecholine is used to restore parasympathetic tone to smooth muscles of the intestinal tract and bladder following abdominal surgery. Pilocarpine is used to constrict pupils and reduce pressure caused by glaucoma. Pilocarpine contracts the ciliary muscle with causes the iris to be withdrawn. This action permits drainage of the aqueous humor and thus relieves the pressure due to a glaucoma condition.

Cholinergic Poison agents which mimic the structure of acetylcholine include two poisons: muscarine - an alkaloid present in poisonous mushrooms and nicotine from cigarettes. Muscarinic effects are those of parasympathetic overactivity and include bradycardia, pinpoint pupils, sweating, blurred vision, excessive lacrimation, excessive bronchial secretions, wheezing, dyspnoea, coughing, vomiting, abdominal cramping, diarrhea, and urinary and fecal incontinence.

Nicotine: Nicotinic effects are those of sympathetic overactivity and neuromuscular dysfunction and include tachycardia, hypertension, dilated pupils, muscle fasciculation and muscle weakness.

Accidental ingestion of these poisons may produce death from heart failure unless treated with a suitable antidote. Atropine blocks the receptor site to decrease the stimulant effects produced by the muscarine type poisons, but has no effect on nicotine receptors. 

Cholinergic Drugs II

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Indirect Acting Cholinergic Stimulating Agents:

Acetylcholine Esterase Inhibitors:

Indirect stimulation of cholinergic nerves occurs by inhibiting the cholinesterase enzyme, thus permitting a build up of acetylcholine on the nerve receptor sites. As a result, acetylcholine increases in quantity with successive nerve impulses so that large amounts of acetylcholine can accumulate and repetitively stimulate receptors.

The active site in the enzyme probably has similar characteristics to the nerve receptor sites. However, the two sites are sufficiently different since chemicals which inhibit the enzyme do not effect the nerve receptor site. The active center of acetylcholinesterase consists of a negative subsite, which attracts the quaternary group of choline through both coulombic and hydrophobic forces, and an esteratic subsite, where nucleophilic attack occurs on the acyl carbon of the substrate.

A few drugs are of therapeutic use: neostigmine, physostigmine, and diisopropyl fluorophosphate, all inactivate acetylcholinesterase. These drugs have only a few clinical uses, mainly in augmenting gastric and intestinal contractions (in treatment of obstructions of the digestive tract), in generally augmenting muscular contractions (in the treatment of myasthenia gravis), and in constricting the eye pupils (in the treatment of glaucoma).

Acetylcholine Stimulation:

Cholinesterase inhibitors act indirectly by preventing the enzyme from hydrolyzing (inactivating) acetylcholine at the receptor site. This inhibition permits the buildup of acetylcholine and results in more intensive and prolonged activation of the receptor site. The effects of cholinergic stimulation include: vasodilattion of blood vessels; slower heart rate; constriction of bronchioles and reduced secretion of mucus in the respiratory tract; intestinal cramps; secretion of salvia; sweat and tears; and constriction of eye pupils.

Acetylcholine Inhibitors - Toxic Poisons

The main agents in this class are poisons such as organophosphate insecticides and nerve gases. 

Organophosphorus pesticides and Carbamate pesticides 

Organophosphorus warfare nerve agents: Sarin, Soman, Tabun

Organophosphates:

Organophosphates account for about half (by amount sold) of

all insecticides used in the U.S. In addition to major crops such as cotton, corn, and wheat, they are used on many important minor crops. Some also are used for mosquito control to protect public health against diseases such as malaria, dengue fever, and encephalitis. These insecticides are developed to be highly toxic to the target species, while being much less toxic to non-target species, such as domestic animals and humans.

These compounds, as irreversible cholinesterase inhibitors, are effective in very low concentrations and are capable of causing death within minutes of exposure. The toxicity of organophosphates and carbamates in humans is characterized by a variety of symptoms, including tension, anxiety, headaches, slurred speech, tremor, convulsions, and even death. If death occurs, it is caused by asphyxia resulting from respiratory failure.

The structural similarities to acetylcholine should be examined in the graphic on the left. Well known organophosphates include, malathion and parathion. A carbamate, carbaryl - Sevin, is also shown.

Although organophosphates are relatively toxic to both insects and man, they do not persist in the environment since the phosphate ester is relatively easily hydrolyzed by water. 

Organophosphorus Warfare Nerve Agents:

On March 20, 1995 sarin nerve gas was released in the Tokyo subway system, killing eleven and injuring over 5500 innocent Japanese citizens. Fortunately, the authorities responded quickly and treatment was administered effectively or else many more may have died. This incident was a follow up to the release of sarin in Matsumoto, Japan that killed seven and injured another 200 people.

A organophosphate such as Sarin interacts with cholinesterase, thus preventing it from doing what it is suppose to: breaking down acetylcholine. Now, since acetylcholine is being built up, the receptors nerves get fired off repeatedly thereby causing the muscles, organs and, glands to be overstimulated. If death occurs, it is caused by asphyxia resulting from respiratory failure.

Other nerve gases are Tabun, Soman, and VX. VX is the most toxic and long lasting of the nerve gases.

The molecule pralidoxime (lower graphic) is a useful antidote for intoxication with cholinesterase inhibitors such as the organophosphates. Pralidoxime, has been shown to regenerate functional AChE from the phosphorylated form, thereby reversing the effects of the organophosphates. The pralidoxime oxygen attacks the phosphorous atom of the nerve agent, freeing it from the AChE active site. The molecule removes the inhibitor from the active site in the form of an oxime phosphonate. Atropine (next panel down graphic) also is used to block responses due to excess acetylcholine. In addition, valium often is given as an antidote in conjunction with atropine to counteract seizures which may develop due to elevated levels of acetylcholine.

In moderate-to-severe cases of cholinergic syndrome due to organophosphorus pesticide or warfare agent poisoning, an acetylcholinesterase reactivator should be administered (if available) following atropine. Either pralidoxime or obidoxime are suitable.

The most effective treatment for sarin poisoning is a combination of atropine and oxime given intravenously as soon after exposure as is possible 

Cholinergic Blocking Agents - Antagonists:

Cholinergic blocking agents are compounds which prevent acetylcholine from stimulating the receptor site and thus act as antagonists. These compounds compete with acetylcholine for receptor sites. They do not themselves produce an excitant effect but rather limit the excitant effects of acetylcholine.

The cholinergic nerve depressant effects are as follows: secretions from exocrine glands such as salvia, sweat, and gastric acid in the stomach are decreased; tone and movements of smooth muscles in the gastrointestinal tract and respiratory bronchioles are reduced at high doses; death may result from respiratory failure; pupils are dilated; and paralysis of eye muscles changes the shape of the lens. Since acetylcholine is a neurotransmitter in the central nervous system, it is not surprising that behavioral changes may occur. Although normal doses of atropine produce no behavioral effects, toxic doses produce euphoria and delirium.

Scopolamine, a compound closely resembling atropine, produces drowsiness and amnesia. This drug is used in non-prescription sleeping pills such as Compoz and Sominex. Toxic doses have the same effect as atropine.

Therapeutic use of atropine and related compounds produce the afore mentioned pharmocological effects. It is used as a preoperative medication to prevent salivary and bronchial secretions stimulated by general anesthetics. It is used in gastrointestinal disorders for antisecretory effects in ulcers and antispasmodic effects in diarrhea. Atropine may also be used prior to eye examinations.

Atropine can be used as an antidote for organophosphate poisoning caused by inhibition of cholinesterase. The atropine serves as an effective blocking agent for the excess acetylcholine but does nothing to reverse the inhibition of the cholinesterase.

There are several ways in which to treat patients who have been exposed to organophosphates. One way is to inhibit the action of acetylcholine. This inhibition is accomplished by administering a cholinergic antagonist. These antagonists bind to the post-synaptic acetylcholine receptors, thereby preventing the opening of ion channels. These ion channels, when opened, cause the post-synaptic cells to become depolarized, generating action potentials. The most common antagonist used to treat organophosphorus exposure is atropine. Atropine is naturally found in the deadly nightshade plant, and it is ordinarily a potent neurotoxin. However, when administered in response to organophosphate exposure, it prevents the acetylcholine that has built up in the neuromuscular junction from binding to its receptor. This inhibition effectively suppresses the excess acetylcholine.

Botulinum toxin resulting from bacteria in improperly preserved foods acts by preventing release of stored acetylcholine from all cholinergic nerve endings. Nerve impulses are prevented from reaching the muscles causing respiratory paralysis and death.

Botox is currently an approved treatment to remove facial wrinkles, but must be repeated every several months.

INTRODUCTION TO PHARMACEUTICAL DOSAGE FORMS

Download the powerpoint presentation (.ppt) here for free!

Dosage Forms: Suppositories

To have a copy of the 5-page lecture, download it here.

DOCUMENT OVERVIEW

Suppositories

 Derived from the Latin term supponere, meaning “to place under”.

 SUB – under ; PONERE – to place

 Are solid dosage forms intended for insertion into body orifices where they melt, soften, or dissolved and exert localized or systemic effects.

CLINICAL PHARMACOKINETICS

Before using drugs for therapeutic intervention in individual patients, the

following decisions must be made.

1. the choice of drug must be made (e.g. drug, dosage form & route of administration)

2. an observable pharmacological effect or end point may be selected (e.g. lowering of fever, normalize heart rate)

3. rate of drug input manipulated until their end point is achieved (e.g. therapeutic drug monitoring)

• With an intended effect (as well as the known unintended toxic/side effects) after drug has been administered, one must increase or decrease drug input rate (e.g. size of dose & dosing frequency).
• The point here is that lack of observable effect for drugs could cause the adjustments in drug input rates to be implemented and without knowing whether such changes will benefit the patient.

For example, remember your 64 year-old patient with renal failure receiving Gentamycin treatment for sepsis. You don’t see him improving with your current dose (80mg OD) so you decide to increase it to 80mg BID but you know that the drug is also nephrotoxic and has a narrow therapeutic window. A little adjustment could produce more harm than treatment and you can’t determine this by just looking at your patient.

• A target concentration is needed to decide any change in drug input rate or when pharmacological endpoint cannot be monitored. 

• Therefore, an alternative approach is to define a TARGET CONCENTRATION (it should be within the therapeutic window as set by the MEC and MTC) of drug rather than an observable effect as the end point.

• The plasma concentration of the drug is usually selected because a patient's tissue samples cannot be obtained or the location of the specific site to be sampled may be uncertain.

When is there a need to define Target Concentration?

1. Pharmacological end point is not visible (e.g. small or large improvement of sepsis with antibiotic treatment, can you determine that?)

2. The TI is narrow. (near to 1, therapeutic window is narrow, for example MTC-MEC=0.00023)

3. When drug input needs to be manipulated due to changes in patient response

4. If it is not possible to visualize an organ

5. When it is not justified to take tissue samples or when it is difficult to extract tissue samples to monitor drug levels objectively (again, you already know this).


In providing instructions for the treatment of a patient, the following must be specified:

1. the dosing schedule (e.g. OD, BID, QID)

2. the choice of drug

3. mode and route of administration must be specified


Pharmacokinetic considerations have a major role in the following:

1. establishing the dosing schedule

2. adjusting an existing dosing schedule

3. to increase effectiveness of the drug

4. to reduce symptoms of toxicity

Remember your “AIM”

Coating Tablet Defects: The Cause and The Remedies

Here is a list of common defects associated with coated tablets and some likely causes and the remedies.

Picking and sticking
This is when the coating removes a piece of the tablet from the core. Overwetting or examples or excessive film tackiness causes tablets to stick to each other or to the coating pan. On drying, at the point of contact, a piece of the film may remain adhered to the pan or to another tablet, giving a “picked” appearance to the tablet surface and resulting in a small exposed area of the core. It is caused by over-wetting the tablets, by under-drying, or by poor tablet quality.

REMEDY: A reduction in the liquid application rate or increase in the drying air temperature and air volume usually solves this problem. Excessive tackiness may be an indication of a poor formulation.


Twinning
This is the term for two tablets that stick together, and it’s a common problem with capsule shaped tablets.

REMEDY : Assuming you don’t wish to change the tablet shape, you can solve this problem by balancing the pan speed and spray rate. Try reducing the spray rate or increasing the pan speed. In some cases, it is necessary to modify the design of the tooling by very slightly changing the radius. The change is almost impossible to see, but it prevents the twinning problem.


Color Variation
This problem can be caused by processing conditions or the formulation. Improper mixing, uneven spray pattern and insufficient coating may result in color variation. The migration of soluble dyes, plasticizers and other additives during drying may give the coating a mottled or spotted appearance.

REMEDY:
1. The use of lake dyes eliminates dye migration.
2. A reformulation with different plasticizers and additives is the best way to solve film instabilities caused by the ingredients.


Orange Peel
This refers to a coating texture that resembles the surface of an orange. Inadequate spreading of the coating solution before drying causes a bumpy or “orange-peel” effect on the coating.
It is usually the result of high atomization pressure in combination with spray rates that are too high. This also indicates that spreading is impeded by too rapid drying or by high solution viscosity.

REMEDY: Thinning the solution with additional solvent may correct this problem.


Mottled color
This can happen when the coating solution is improperly prepared, the actual spray rate differs from the target rate, the tablet cores are cold, or the drying rate is out of specification.


Capping and Lamination
This is when the tablet separates in laminar fashion. Capping is partial or complete separation of top or bottom crowns of tablet main body. Lamination is separation of a tablet into two or more distinct layers. Friability test can be used to reveal these problems

The problem stems from improper tablet compression, but it may not reveal itself until you start coating. How you operate the coating system, however, can exacerbate the problem.

REMEDY : Be careful not to over-dry the tablets in the preheating stage. That can make the tablets brittle and promote capping.


Roughness
A rough or gritty surface is a defect often observed when coating is applied by a spray. Some of the droplets may dry too rapidly before reaching the tablet bed, resulting in the deposits on the tablet surface of “spray dried” particles instead of finely divided droplets of coating solution. Surface roughness also increases with pigment concentration and polymer concentration in the coating solution.

REMEDY: Moving the nozzle closer to the tablet bed and reducing the degree of atomization can decrease the roughness due to “spray drying”.


Hazing / Dull Film
This is sometimes called Bloom. It can occur when too high a processing temperature is used for a particular formulation. Dulling is particularly evident when cellulosic polymers are applied out of aqueous media at high processing temperatures. It can also occur if the coated tablets are exposed to high humidity conditions and partial salvation of film results.


Bridging
This occurs when the coating fills in the lettering or logo on the tablet and is typically caused by improper application of the solution, poor design of the tablet embossing, high coating viscosity, high percentage of solids in the solution, or improper atomization pressure. During drying, the film may shrink and pull away from the sharp corners of an intagliation or bisect, resulting in a “bridging” of the surface. This defect can be so severe that the monogram or bisect is completely obscured.

REMEDY: Increasing the plasticizer content or changing the plasticizer can decrease the incidence of bridging.


Filling
Filling is caused by applying too much solution, resulting in a thick film that fills and narrows the monogram or bisect. In addition, if the solution is applied too fast, Overwetting may cause the liquid to quickly fill and be retained in the monogram.

REMEDY: Judicious monitoring of the fluid application rate and thorough mixing of the tablets in the pan can prevent filling.


Erosion
This can be the result of soft or friable tablets (and the pan turning too fast), an over-wetted tablet surface, inadequate drying, or lack of tablet surface strength.


Peeling and frosting
This is a defect where the coating peels away from the tablet surface in a sheet. Peeling indicates that the coating solution did not lock into the tablet surface. This could be due to a defect in the coating solution, over-wetting, or high moisture content in the tablet core which prevented the coating to adhering.


Chipping
This is the result of high pan speed, a friable tablet core, or a coating solution that lacks a good plasticizer


Blistering
When coated tablets require further drying in ovens, too rapid evaporation of the solvent from the core and the effect of high temperature on the strength, elasticity and adhesion of the film may result in blistering.

REMEDY: Milder drying conditions are warranted in this case.


Cracking
It occurs if internal stresses in the film exceed the tensile strength of the film.

REMEDY: tensile strength of the film can be increased by Using higher molecular weight polymers or polymer blends.